Molecular Biology: Protein Structure and Function - Stepanov V.M. 2005

Tertiary protein structure
Hydrophobic core

Typically, the hydrophobic core consists exclusively of hydrophobic side chains, with hydrophilic or charged amino acid residues only rarely embedded within it. Such exceptions are generally considered to be driven by specific functional requirements.

The hydrophobic core, which—as noted earlier—does not necessarily approach a spherical configuration but remains more or less compact, typically accounts for 20-30% of the total number of amino acid residues. It is particularly rich in bulky residues such as leucine, isoleucine, phenylalanine, and valine. For instance, DNase I, whose polypeptide chain consists of 259 amino acid residues, forms three hydrophobic cores during structural folding, containing 70% of all hydrophobic residues present in this protein. The tendency of hydrophobic side chains (primarily Alanine, valine, isoleucine, leucine, phenylalanine, and Methionine) to become embedded within the interior of the enzyme's globule, which is typical of Proteins in general, is illustrated in Table 6.1.

Class="center">Table 6.1 Water accessibility of amino acid side chains in DNase I

Table 6.2 Proportion of amino acid residues that become buried and practically inaccessible to the solvent following protein folding

The generality of the tendency for hydrophobic side chains to be buried within the globule is confirmed by an Analysis of the spatial structures of 9 proteins containing a total of 2,000 amino acid residues, of which 587 (29%) are buried, i.e., form hydrophobic cores (Table 6.2).

The packing of amino acid side chains within the hydrophobic core is generally close to tight (Fig. 6.2), which maximizes Structure/103.html">Van der Waals interactions between hydrocarbon structures—an additional factor stabilizing the Spatial Structure. In evolutionarily related proteins with homologous tertiary structures, the volume of the hydrophobic core remains largely invariant; The Emergence of larger side groups is compensated by Mutations that reduce the volume of neighboring interacting side chains. Nevertheless, it would be incorrect to attribute the stabilizing effect of the hydrophobic core solely to its volume, as structural Organization plays a critically important role.

Fig. 6.2. Cross-section (Cleavage) of a hen egg-white Lysozyme model.

1 — distinctly polar groups; 2 — moderately polar; 3 — hydrophobic. It can be seen that the latter are concentrated in the interior of the globule, though they may occasionally emerge onto the surface, notably within the cleft of the Active Site (top left). Polar residues form the outer shell, occasionally penetrating into the interior of the globule (e.g., bottom left)

A striking example is the exquisite sensitivity of the stability of bacteriophage f1 Gene V protein and its mutants to The Nature of the Amino Acids Forming the hydrophobic core. Thus, replacing isoleucine-47 with valine removes a single methyl group from the hydrophobic core, whereas replacing valine-35 with isoleucine introduces an additional methyl group. Consequently, in the double mutant Ile-47 → Val; Val-35 → Ile, the volume of the hydrophobic core remains identical to that of the wild-type protein, although the packing of the hydrophobic groups within the core is naturally altered to some extent. Both single mutants (Ile-47 → Val and Val-35 → Ile) as well as the aforementioned double mutant resemble the wild-type protein in Structure and function, yet are significantly less stable.

The hydrophobic core is surrounded by an outer shell that remains in contact with water. This shell contains hydrophilic amino acid residues alongside a substantial proportion of hydrophobic amino acid side chains—up to half of their total content. These often form distinct hydrophobic patches or "flutings" that give the protein surface a mosaic character, interspersed with strictly hydrophilic regions. Such exposed hydrophobic patches can have functional significance, forming the hydrophobic surfaces of binding sites for substrates and other ligands, and participating in Protein-Protein Interactions, particularly in the stabilization of quaternary structure.

Naturally, the boundaries between the hydrophobic core and the protein's surface layer are not strictly demarcated; furthermore, water molecules are frequently found embedded within the spatial structure, contributing to the Maintenance of the intramolecular hydrogen-bonding network by acting as bridges between the Functional groups of amino acid side chains.